Compounds consisting in particular of effectors of the central nervous system receptors sensitive excitatory amino acids, preparation and biological applications

ABSTRACT

The invention concerns compounds of formula (I):                    
     in which: R 1  to R 4 , identical or different, represent hydrogen, alkyl or aryl, themselves substituted if required, R 1  and R 2  together further capable of representing a bridge —(CH 2 ) m  in which m is a whole number from 1 to 5, or a bridge X representing a linear combination of m hydrocarbon groups, m being as defined above and comprising, if required, at least a heteroatom such as O, N or S, or a bridge X representing a linear combination of p heteroatoms O, N and/or S, in which p is a whole number from 1 to 3; A 1  and A 2  represent —COOH, —SO 3 H or —PO 3 H 2  radicals, or their derivatives such as esters or amides, or only one of A 1  or A 2  has these meanings, when R 1  and R 2  represent a single bond between the carbons in positions 3 and 4, the other of these groups being a hydrogen atom; Y represents a chain —(CH 2 ) n —, n being zero or a whole number from 1 to 5, or represents a linear combination of n hydrocarbon groups and at least a heteroatom O, N or S, or a linear combination of q heteroatoms O, N and/or S, in which q is a whole number from 1 to 3. The invention is applicable as medicines.

This application is a 371 of PCT/FR98/00256 filed Feb. 10, 1998/

BACKGROUND OF THE INVENTION

A subjet of the invention is compounds in particular constitutingeffectors of central nervous system effectors sensitive toneuroexcitatory amino acids (NEAA's), in particular glutamate (Glu),their preparation and their biological uses.

It relates more particularly to agonist, antagonist or reverse agonistcompounds of these receptors.

It is known that glutamate is involved in numerous cerebral functions.

Important roles are therefore attributed to glutamatergic receptors, inparticular in the conduction of nerve impulse, synaptic plasticity, thedevelopment of the central nervous system, learning and memory.

Glutamate is also the main endogenous neurotoxin, being responsible forthe neuronal death observed after ischemia, hypoxia, epileptic fits ortraumatisms of the brain. It is not therefore surprising that glutamatereceptors are considered to be involved in various disorders of thecentral nervous system and neurodegenerative diseases.

The usefulness can therefore be measured of having means of modulatingthe effects of the glutamate in the central nervous system by usingglutamatergic receptors as targets.

Two main types of glutamatergic receptors have been characterized:ionotropic receptors and metabotropic receptors. The ionotropicreceptors are cationic channels activated by the glutamate and directlyresponsible for the rapid depolarization of post-synaptic cells. Theyare compounds of different sub-units and classified into three groupsaccording to their pharmacological and functional properties. Adistinction is thus made between the NMDA receptors (N-methyl-D-asparticacid), AMPA (α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid) andkainate. Metabotropic receptors (mGluRs) have been revealed morerecently (1985), and have been studied in less depth owing to their lackof specific effectors, until the discovery of 1-amino cyclopentane 1,3dicarboxylic acid or ACPD. They regulate the activity of the ionicchannels or enzymes producing second messengers via G proteins bindingthe GTP. Although they are generally not directly involved in rapidsynaptic transmission, these receptors modulate the efficacy of thesesynapses by regulating either the ionic post-synaptic channels and theirreceptors, or the release or recapture of the glutamate. The mGluRstherefore play an important role in particular in the induction of thelong-term potentialization (LTP) and the long-term depression (LDP) ofsynaptic transmission, in the regulation of baroceptive reflexes,spatial learning, motor learning, postural and kinetic integration. Theyare probably also involved in acute or chronic degenerative diseasessuch as epilepsy, Alzheimer's disease, Parkinson's disease orHuntington's chorea.

To date, eight mGluRs have been cloned and can be classified into 3groups according to their sequence homologies, their pharmacologicalproperties and their signal transduction mechanisms.

The metabotropic receptors are very useful as targets for the modulationof the effects of glutamate, but their role in various physiologicalresponses involving glutamate remains poorly characterized to date owingto the absence of totally specific tools. Different ligands, analoguesof glutamic acid, have been recently described and are used for thepharmacological and physiological characterization of the metabotropicreceptors, but turn out to be insufficiently selective and do not allowa perfect differentiation between groups or, within a group, of thesub-group to which the receptor belongs.

There is a requirement for new molecules allowing the differentiationbetween the ionotropic and metabotropic receptors. It is also importantto have more selective molecules available which, within themetabotropic receptor family, allow these receptors to be sought andstudied, the bioactive structures specific to each receptor to bedefined and new pharmacologically active molecules to be produced.

In this context, the inventors have studied cyclic analogues of glutamicacid with a restricted conformation and have observed that the presenceof certain groups in specified positions, with the resultingstereochemical possibilities, led to compounds endowed with strengthenedand/or new activities vis-à-vis the glutamatergic receptors.

BRIEF SUMMARY OF THE INVENTION

A purpose of the invention is therefore to provide new compounds endowedwith advantageous effects vis-à-vis the receptors of the central nervoussystem.

It also aims to provide a process for synthesizing these compounds whichis easy to implement and can be exploited on an industrial scale.

It also aims to make use of the properties of these new compounds forproducing agonist or antagonist agents of these receptors, which can beused as research and study tools, or as medicaments.

The compounds of the invention are characterized in that they correspondto formula (I)

in which

R₁ to R₄, identical to or different from each other, represent ahydrogen atom, an alkyl radical or an aryl radical, these radicalsthemselves being substituted where appropriate, R₁ and R₂ together beingable to further represent a —(CH₂)_(m) ³¹ bridge, where m is an integerfrom 1 to 5, or a bridge X representing a linear combination of mhydrocarbon groups, m being as defined above, and where appropriatecomprising at least one heteroatom such as O, N or S, or a bridge Xrepresenting a linear combination of p heteroatoms O, N and/or S, wherep is an integer from 1 to 3,

A₁ and A₂ represent —COOH, —SO₃H or —PO₃H₂ radicals or their derivativessuch as esters or amides or, when R₁ and R₂ represent a single bondbetween the carbons in positions 3 and 4, A₁ or A₂ has the abovemeanings, the other of these groups being a hydrogen atom,

Y represents a hydrocarbon chain —(CH₂)_(n)—, n being nil or an integerfrom 1 to 5, or represents a linear combination of n hydrocarbon groupsand at least one heteroatom O, N or S, or a linear combination of qheteroatoms O, N and/or S, where q is an integer from 1 to 3.

A preferred family is formed by monocyclic compounds. These arecompounds of formula I in which Y and the carbons carrying R₁ and R₂ arenot linked together in forming one of the aforementioned bridges.

In another family of the invention, the compounds are also monocyclicand correspond to formula I above, in which the carbons carrying R₁ andR₂ are not linked together in forming one of the aforementioned bridges,and Y represents a group or a combination as defined above.

In yet another family of the invention, the compounds are bicyclic andcorrespond to formula I above in which X or both X and Y are present andare defined as indicated above.

In a preferred group of compounds of these different families, A₁ and A₂are identical. In preferred compounds of this group, A₁ and A₂ bothrepresent a carboxyl group, or the corresponding esters or amides.

In another group, A₁ and A₂ are as defined above, but are different fromeach other.

Advantageous compounds of these families and groups include R₁, R₂,and/or R₃ and R₄ substituents representing an alkyl or aryl radical,these radicals being substituted where appropriate.

By “alkyl” radical is understood according to the invention a radical of1 to 10 carbon atoms, in particular 1 to 5 carbon atoms. By “aryl”radical is understood a mono- or polycyclic aromatic radical. Apreferred aryl radical is constituted by the phenyl radical.

The alkyl or aryl radicals can be substituted, for example, by a halogenatom or a hydroxyl group.

In other advantageous compounds, R₁ and R₂ and/or R₃ and R₄ represent ahydrogen atom.

The compounds defined above can exist as achiral or chiral molecules, inthe form of different diastereoisomers, optionally as racemic, whereappropriate in the form of one of the enantiomers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a to 1 c show activation of mGluR receptors by ACPT's.

FIG. 2 illustrates inhibition by ACPT's of the formation of IP inducedby Glu.

FIGS. 3a to 3c show determination of the antagonist effect and of theACPT-II inhibition constant, at different concentrations, on themGluR's, and FIGS. 3d to 3 f, the corresponding Shild graphicrepresentations.

FIGS. 4a to 4 c illustrate the antagonist effect of ACPT-III isomers onmGluR's.

FIG. 5 shows the reverse agonist effect of ACPT on mGluR1a.

DETAILED DESCRIPTION OF THE INVENTION

The invention in particular relates to 1-amino-cyclopentane -1,3,4tricarboxylic acids ACPT-I, ACPT-II, ACPT-IIIa and ACPT-IIIb whichcorrespond respectively to the following formulae (II), (III), (IVa) and(IVb):

The invention also relates to a process for synthesizing the compoundsdefined above.

This synthesis, advantageously carried out according to Bucherer-Bergs'or Strecker's reaction, is characterized in that it comprises

operating according to Bucherer-Bergs' technique, the reaction of aketone of formula (V)

in which R₁ to R₄ and n are as defined in formula I and A₃ and A₄represent a —COOR₅, PO₃(R₅)₂ PO₃HR₅ or SO₃R₅ group, where R₅ is ahydrogen atom or an alkyl radical,

with a cyanide and a basic ammonium carbonate, or

operating according to Strecker's technique, the reaction of the ketone(V) with an ammonium salt and a cyanide, then the addition of ammoniumcarbonate to the reaction mixture, these reactions being carried outunder conditions leading to a hydantoin of formula (VI)

followed by hydrolysis of the hydantoin thus obtained, or of a hydantoinderivative in which the —NH groups are blocked by protective groups,this hydrolysis leading to

obtaining a mixture containing various diastereoisomers,

separation of the different compounds, and resolution of the racemics ifdesired.

In one embodiment, the ketone (V) is reacted with ammonium carbonate anda cyanide, and after a heating stage, the resulting reaction mixture isacidified.

The ketone is in solution in an organic solvent of alcohol type, inparticular in methanol.

Amimonium carbonate is used in an excess of 3 to 10 equivalents withrespect to the ketone, preferably approximately 5 equivalents.

As an appropriate cyanide, there can be mentioned the mineral cyanides,such as sodium or potassium cyanide. The cyanide is used at a rate of 1equivalent or in slight excess with respect to the ketone.

The reaction mixture obtained by adding the above compounds, preferablyin the form of an aqueous solution, to the ketone is brought to atemperature greater than 40° C. and lower than approximately 90° C.

Heating the mixture can be carried out within a first temperature range,with a cooler, then carried out at a higher temperature, without acooler, in order to eliminate the excess ammonium salt.

Satisfactory results were obtained by heating the mixture forapproximately 8 to 15 hours at approximately 50 to 70° C., in particularat approximately 55-60° C., with a cooler, then at a temperature of theorder of 75 to 90° C., for 0.5 to 3 hours, in particular atapproximately 80° C., for 1 hour, without a cooler.

The reaction mixture is then acidified. The mixture is subjected forexample to agitation after the acid is added, which leads to choosing areaction time of the order of 10 to 60 minutes, in particularapproximately 15 to 30 minutes. The acid is advantageously added inorder to obtain a pH of approximately 3 to 4.

In another embodiment, the hydantoins are obtained by firstly adding anammonium salt, for example ammonium chloride, and a cyanide to thestarting ketone (V) in order to form the corresponding aminonitrilederivative, then by adding ammonium carbonate, followed, after reaction,by the acidification of the mixture.

The ketone is then more particularly used in an aqueous solution. Theammonium salt and the cyanide, also in an aqueous solution, are added tothe ketone. By operating at ambient temperature, and under agitation,the reaction allowing the corresponding aminonitriles to be obtained iscarried out over approximately 1 to 3 days.

Ammonium carbonate is then added to the reaction mixture then, afteragitation for several hours, the solution obtained is acidified to a pHof approximately 3 to 4.

The conversion of the hydantoins to the corresponding amino acids iscarried out by hydrolysis.

In a variant, an acid or basic solution is added to the hydantoinpreviously obtained.

Preferably, the acid solution containing the hydantoin is evaporated todryness beforehand and the residue subjected to an extraction phase inorder to eliminate at least part of the salts.

Extraction is carried out for example using an alcohol such as methanol.

The filtrate recovered is evaporated and dissolved in the acid or basicsolution and subjected to a heating stage. 2 to 8 N, preferably 6 Nhydrochloric acid or sulphuric acid, or 2 to 8 N, preferably 6N soda orpotash or barium hydroxide in a saturated solution is advantageouslyused.

By operating in a closed vessel at a temperature greater than 50° C., inparticular approximately 100 to 130° C., in particular of the order of110° or 120° C., the treatment is carried out over several days, inparticular 2 to 6 days.

In another variant, the —NH groups of the hydantoins are first blockedby protective groups, then the derivative obtained in this way issubjected to a controlled basic hydrolysis stage.

The hydantoin solution obtained at the end of the synthesis stagepreviously described is evaporated to dryness and the resultinghydantoin is esterified, for example by dry 1N HCl in methanol. Afterevaporation, the residue is taken up in an organic solvent such as ethylacetate, and washed with a saturated salt solution. The organic phasecontains the hydantoin esters.

The esterified hydantoin is subjected to an evaporation stage then adrying stage, and dissolved in an organic solvent such as CH₃CN.

In order to block the —NH groups, an alkyl-carbamate is formed in thepresence of dimethyl-aminopyridine (DMAP).

This protection is carried out particularly advantageously in the formof butyloxycarbonyl derivatives using di-t-butyldicarbonate (Boc).

After approximately 1 to 2 hours of reaction, the blocked compound isrecovered, for example after passage through a chromatography column.

The hydantoin protected in this way is dissolved in acetonitrile, and itis hydrolyzed by adding a base such as lithium hydroxide, preferably inthe form of a solution of 1N concentration, followed by neutralizationwith an acid such as 1N HCl, evaporation to dryness and the residue istreated with an acid solution constituted for example by HCl/CH₃COOH.

Separation of the diastereoisomers of the mixture of amino acids isadvantageously carried out by chromatography on an anion exchangecolumn.

Advantageously, this stage is preceded by purification carried out bycation exchange chromatography.

Different choices will be made for implementing the process of theinvention:

the choice between Bucherer-Bergs' or Strecker's reaction is dictated bythe choice of a preferential cis or trans configuration (position of the—COOH group in position 1 with respect to A₁ and A₂), (this is the casefor example for meso amino acids),

that of the stereochemistry of the starting ketone by the desired finalconfiguration for the compounds to be synthesized (case of the aminoacids where A₁ and A₂ have a trans relative configuration for example).

Study of the biological activities of the compounds of the inventionvis-à-vis the receptors of the central nervous system sensitive toglutamate has demonstrated their specificity vis-à-vis the metabotropicreceptors.

Tests carried out using these compounds have in fact shown that they donot display any agonist or antagonist activity on ionotropic receptors(tests carried out at 1 mM on granule cells of the cerebellum, normallyactivated by NMDA or kainate 100 μM).

On the other hand, these compounds display an agonist or antagonisteffect vis-à-vis the metabotropic receptors, as demonstrated by theresults given in the examples. According to a very useful aspect, thisreaction is selective, for a given compound, with respect to a sub-groupof receptors.

Thus, ACPT-I is an agonist of mGluR4. ACPT-II is a general antagonist ofall the mGluR's tested (mGluR1a, mGluR2 and mGluR4a) and is endowed withreverse agonist properties on mGluR1. ACTP-IIIa is an antagonist ofmGluR4, and ACTP-IIIb an agonist of mGluR4, these two ACTP-IIIa and IIIbbeing antagonists of mGluR1 and mGluR2.

The invention therefore relates to the use of the compounds definedabove as specific agonist or antagonist agents of metabotropicglutamatergic receptors.

These agents can more particularly be used as tools for specificallystudying each of the groups and sub-groups of metabotropic receptors bydifferentiating them and thus allowing definition of their respectivespecific physiological roles.

Applications based on the use of such tools include the putting thecompounds defined above in contact with cell cultures expressing saidreceptors, under conditions allowing the realization of the agonist,antagonist or reverse agonist reaction to be studied.

The advantageous effects of the compounds of the invention areaccompanied by substantial harmlessness as demonstrated by the testscarried out on mice.

The invention therefore relates to the exploitation of the properties ofthese compounds in acid form, or as pro-drugs, their amides or esters,for the production of pharmaceutical compositions.

The pharmaceutical compositions of the invention are characterized inthat they contain an effective quantity of at least one compound asdefined above, in combination with an inert pharmaceutical vehicle.

Where appropriate, these compositions contain active ingredients ofother medicaments.

The compositions of the invention are particularly suitable formodulating the effect of the glutamate, for example in the treatment ofmemory disorders, senile dementia, epilepsy, Alzheimer's disease,Parkinson's disease, peripheral neuropathies and motor disorders.

Packaging with a view to sale, in particular labelling and instructionleaflets, and advantageously the wrapping are designed according to theintended therapeutic use.

The pharmaceutical compositions of the invention can be administered indifferent forms, more particularly by oral or injectable, or also nasalroute.

For administration by oral route, use is made in particular of tablets,pills, lozenges, gelatin capsules, drops or also liposomes. Thesecompositions advantageously contain from 1 to 100 mg of activeingredient per unit dose, preferably from 2.5 to 50 mg.

Other forms of administration include solutions which can be injected byintravenous, sub-cutaneous or intramuscular route, produced from sterileor sterilizable solutions. They can also be suspensions or emulsions.

These injectable forms contain from 0.5 to 50 mg of active ingredient,preferably from 1 to 30 mg per unit dose.

For information, the dosage which can be used in man corresponds to thefollowing doses: the patient may thus be given for example from 5 to 300mg/day, in one or more doses.

Other characteristics and advantages of the invention are given in thefollowing examples in which reference is made to FIGS. 1 to 5 whichrepresent respectively

FIGS. 1a to 1 c: activation of mGluR receptors by ACPT'S,

FIG. 2: inhibition by ACPT's of the formation of IP induced by Glu.

FIGS. 3a to 3 c: determination of the antagonist effect and of theACPT-II inhibition constant, at different concentrations, on themGluR's, and FIGS. 3d to 3 f, the corresponding Shild graphicrepresentations,

FIGS. 4a to 4 c: the antagonist effect of ACPT-III isomers on mGluR's,and

FIG. 5: the reverse agonist effect of ACPT on mGluR1a.

EXAMPLES

These examples relate to ACPT-I (1S, 3R, 4S), ACPT-II (1R, 3R, 4s),(±)-ACPTIII, (3R, 4R)-ACPT-III, and (3S,4S)-ACPT-III. These compoundswere synthesized using Bucherer-Bergs' or Strecker's reaction, from 5,(±)-8, (3R,4R)-8 or (3S,4S)-8 ketoacids (diagrams 1 a and 1 b, 2 and 3hereafter), followed by hydrolysis of the hydantoins formed (diagram 4),and separation of the ACPT's by chromatography on an anion exchanger.

Synthesis of the 5 ketodiester

The operation is carried out according to Gais, H. -J.; Bülow, G.;Zatorski, A.; Jentsch, M.; Maidonis, P.; Hemmerle, H. J., J. Org. Chem.1989, 54, 5115-5122; Hemmerle, H., Dissertation, Universität Freiburg imBrisgau, Germany, 1990.

This synthesis is illustrated in the following diagram:

a: H₂SO₄/MeOH; b: KMnO₄; c:AcONa/Ac₂O, 140° C.

Synthesis of the (±)8 ketodiester

The operation is carried out according to Rosenquist, A.; Kvarnström,I.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. Acta Chem. Scand.1992, 46, 1127-1129.

This synthesis is illustrated in the following diagram 1 b:

d: sealed tube, 100° C. (Sample, T. E.; Hatch, L. F., Org. Synth. Coll.Vol. VI 1988, 454); e: KMnO₄; f: AcONa/Ac₂O, 140° C.

Synthesis of the (3R,4R)-8 and (3S,4S)-8 ketodiesters.

The operation is carried out according to Suemune, H.; Tanaka, M.;Obaishi, H.; Sakai, K. Chem. Pharm. Bull. 1988, 36, 15-21; Rosenquist,A.; Kvarnström, I.; Svensson S. C. T.; Classon, B.; Samuelsson, B. ActaChem. Scand. 1992, 46, 1127-1129.

This synthesis is illustrated in the following diagram 2:

a: pig's liver esterase, pH 7.0; b:CH₃N₂/CH₂Cl₂

Synthesis of the hydantoins by Bucherer-Bergs' or Strecker's method, viathe corresponding aminonitriles.

Strecker's synthesis, starting from the 5 cis-ketoester, results in theintroduction of the aminated group in a slightly more favorableproportion to the product comprising the aminated group in cis positionwith respect to the carboxylates than Bucherer-Bergs' reaction (ACPT-1,approximately 30% instead of 20%, see Example 4).

This synthesis is illustrated by the following diagram 3:

Conversion of the hydantoins to the corresponding amino acids.

Direct hydrolysis of the hydantoins leads to significant epimerizationof one or all of the carboxylic groups in the cis- - - - > transdirection (approximately 25:75 at equilibrium), and can even lead to theracemisation of a trans enantiomer. In order to obtain correctstereochemistry conforming with that of the ketoacid initially used, themethod involving the alkaline hydrolysis of the diBoc derivatives ofhydantoin (Kubik, S.; Meissner, R. S.; Rebek Jr., J. Tetrahedron Lett.1994, 35, 6635-6638) must be preferred, as it only produces minimumepimerization (or racemisation) (see use in the case of the hydantoinoriginating from the 5 cis-ketoester, Example 4, or the hydantoinsoriginating from the enantiomerically pure (3R, 4R)-8 or (3S-4S)-8 transketoesters, Examples 6 and 7).

This synthesis is illustrated by the following diagram 4:

The detailed syntheses of ACPT's starting from the ketodiesters arereported below.

Example 1

(NH₄)₂CO₃ (0.48 g, 5 eq.) and KCN (0.077 g, 1.2 eq.) dissolved in water(1.5 ml) are added to the 5 cis-ketodiester (0.2 g, 1 mmol) dissolved inMeOH 5 (1.5 ml). The mixture is heated overnight at 55-60° C. with acooler, then for 1 hour at 80° C. without a cooler (in order toeliminate the excess (NH₄)₂CO₃) and acidified with a solution ofconcentrated HCl. The acid solution is agitated for 0.5 hour at ambienttemperature. The residue obtained after evaporation to dryness isextracted with MeOH (in order to eliminate part of the salts), theevaporated filtrate (0.23 g) is dissolved in a 6N solution of HCl (20ml) in a tight screw-topped bottle and heated at 110° C. for 5 days. Thesolution is evaporated, diluted with 200 ml of water and deposited at anacid pH (approximately pH 2-3) on a Dowex 50×4 cation exchanger column(H⁺, 20-50 mesh, 2×14 cm). The column is rinsed with water (200 ml) andthe mixture of ACPT's eluted with a 0.5 M ammonium hydroxide solution.The fractions which are positive to ninhydrin are evaporated (0.2 g,0.92 mmol) and the mixture redissolved in boiled water (200 ml) isdeposited at a basic pH (approximately pH 9-10) on an AG1×4 anionexchanger column (AcO⁻, 200-400 mesh, 2×16 cm). After rinsing withboiled water, ACPT-I (10 mg), ACPT-II (30 mg) and (±)-ACPT-III (120 mg)are respectively eluted with a 0.5 M, 0.8 M and 1 M solution of AcOH.Overall yield: 64.1% with respect to the ketodiester.

VPC analysis in the form of N-trifluoroacetyl-O,O′-diisopropyl esters(M. Maurs, C. Ducrocq, A. Righini-Tapie and R. Azerad, J. Chromatogr.,25, 1985, 444-449):

On an OV-1701 capillary column (Flexibond®, Pierce) (15 m×0.2 mm, 0.25mm film thickness) 190° C.: Rt 13.5 minutes [(±)-ACPT-III], 16.4 minutes(ACPT-II), 19.2 minutes (ACPT-I).

On an Ultra-2® capillary column (Hewlett-Packard) (25 m×0.2 mm; 0.33 mmfilm thickness, 2 minutes at 140° C., then a gradient from 140 to 300°C. (10° C./min), then 5 minutes at 300° C.: Rt 13.7 minutes((±)-ACPT-III), 13.9 minutes (ACPT-I), 14.2 minutes (ACPT-II).

On a Chirasil-Val® capillary column (50 m×0.32 mm, 0.2 mm filmthickness) 190° C.: Rt 15.0 minutes [(3S,4S)- ACPT-III] and 15.1 minutes[(3R,4R)-ACPT-III], 18.3 minutes [(1S, 3R, 4S)-(ACPT-II)], 22.4 minutes[(1S, 3R, 4S)-(ACPT-I)] 150° C.: Rt 84.7 minutes [(3S,4S)-ACPT-III] and86.1 minutes [(3R,4R)-ACPT-III].

(1S, 3R, 4S) ACPT-I. GC/MS (EI) m/z (% of basic peak): 352(4), 338(7),296(30), 268(7), 250(26), 222(100), 204(16), 177(27).

¹H NMR (D₂O, NH₄ ⁺ salt) : 3.20 (m, 2H, H-3, H-4), 2.63 (m, 2H, H-2,H-5), 2.24 (m, 2H, H-2, H-5).

¹³C NMR: 183.8 and 179.0 (CO), 70.0 (C-1), 50.8 (C-3, C-4), 42.1 (C-2,C-5).

Anal.: calc. for C₈H₁₁NO₆, 2H₂O, %: C, 37.95; H, 5.97; N, 5.53. found,%: C, 38.61; H, 5.46; N, 5.59.

(1R, 3R, 4S) ACPT-II. GC/MS (EI) m/z (% of basic peak): 380(1), 352(12),338(10), 310(3), 296(21), 268(5), 250(30), 222(100), 204(14), 177(22).

¹H NMR (D₂O, NH₄ ⁺ salt) : 3.33 (m, 2H, H-3, H-4), 2.52 (m, 2H, H-2,H-5), 2.32 (m, 2H, H-2, H-5)

¹³C NMR: 183.6 and 180.4 (CO), 69.2 (C-1), 53.7 (C-3, C-4), 42.3 (C-2,C-5)

Anal: calc. for C₈H₁₁NO₆, 2H₂O, %: C, 37.95; H, 5.97; N, 5.53. found, %:C, 38.53; H, 5.39; N, 5.57.

(±)-ACPT-III. GC/MS (EI) m/z (% of basic peak): 440(0.01), 380(2),352(15), 338(8), 310(14), 296(12), 268(65), 250(20), 222(100), 204(18),177(28).

¹H NMR (D₂O, ³⁰ NH₄ salt): 3.19 (m, 2H, H-3, H-4), 2.59, 2.42 and 2.10(3m, 4H, H-2, H-5).

¹³C NMR: 185.9, 183.9 and 179.2 (CO), 69.9 (C-1), 53.2 (C-3, C-4), 43.3and 42.8 (C-2, C-5).

Anal: calc. for C₈H₁₁NO₆, 2H₂O, %: C, 37.95; H, 5.97; N, 5.53. found, %:C, 38.47; H, 5.31; N, 5.54.

Example 2

cis-ketodiester 5 (0.4 g, 2 mmol) dissolved in MeOH (4 ml) is treatedwith (NH₄)₂CO₃ (0.96 g, 5 eq.) and KCN (0.154 g, 1.2 eq.) as describedin Example 1. The residue obtained after evaporation to dryness isdissolved in a suspension of barium hydroxide (3.0 g in 40 ml of water)in a screw-top bottle and heated at 120° C. for 2 days. The solution iscooled down, acidified with a dilute solution of H₂SO₄, filtered throughcelite, diluted with 200 ml of water and deposited on a Dowex 50×4cation exchanger column (H+, 20-50 mesh, 3×17 cm). The column is rinsedwith water (300 ml) and a mixture of ACPT eluted with a 0.5 M ammoniumhydroxide solution. The fractions which are positive to ninhydrin areevaporated (0.480 g) and the mixture redissolved in boiled water (250ml) is deposited at a basic pH on an AG1×4 anion exchanger column (AcO⁻,200-400 mesh, 3×19 cm). After rinsing with boiled water, ACPT-I (17.2mg), ACPT-II (32 mg) and (±)-ACPT-III (324 mg) are eluted with aceticacid solutions as described in Example 1. Overall yield: 75.1%.

Example 3

(NH₄)₂CO₃ (0.96 g, 5 eq.) and KCN (0.154 g, 1.2 eq.) dissolved in water(3 ml) are added to cis-ketodiester 5 (0.40 g, 2 mmol) dissolved in MeOH(4 ml). The mixture is heated at 55-60° C. with a cooler for 2.5 hoursthen acidified to pH 3≧4 with a solution of dilute HCl. Afterapproximately 15 minutes of agitation at ambient temperature, thesolution is concentrated, diluted with an aqueous solution of NaCl (20ml) and extracted with AcOEt (50 ml×2). The organic phase is dried overNa₂SO₄, evaporated and dried under vacuum (0.407.g, 1.5 mmol, grossyield 75.4%). Di-t-butyldicarbonate (1.15 ml, 3 eq.) and DMAP (15 mg,0.08 eq.) [Kubik, S.; Meissner, R. S.; Rebek Jr., J. Tetrahedron Lett.1994, 35, 6635-6638] are added to the mixture of hydantoins dissolved inCH₃CN (20 ml). After 1.5 hours, the solvent is evaporated off, theresidue taken up in CH₂Cl₂, rapidly filtered through a small silicacolumn (2×13 cm) and eluted with CH₂Cl₂ (60 ml), then CH₂Cl₂/AcOEt (4:1)(150 ml). The diBoc-ester detected on a thin layer using TDM (VonArx,E.; Feyel, M.; Brugger, M. J., J. Chromatogr. 1976, 120, 224-228) isevaporated (0.533 g, 1.13 mmol) then dissolved in CH₃CN (3 ml) and 1NLiOH (12 ml). The cloudy solution is agitated for 5 hours at ambienttemperature, cooled down to 0° C., neutralized with 1N HCl (12 ml) andevaporated to dryness. The residue is treated with a solution of gaseousHCl (˜1N) in acetic acid (0.5 hour) then evaporated to dryness. Themixture of ACPT-I, II and III is dissolved in water (1 l) adjusted to pH4 using NaHCO₃ if necessary, purified on a Dowex 50×4 column (H⁺, 20-50mesh, 3×17 cm) (0.177 g) then separated on an AG1×4 (AcO⁻, 200-400 mesh)as described previously, in order to produce ACPT-I (0.035 g), ACPT-II(0.116 g) and (±)-ACPT-III (0.029 g). Overall yield: 36.1 %.

Example 4

NH₄Cl (1.08 g, 10 eq.) and KCN (0.13 g, 1 eq.) are added tocis-ketodiester 5 (0.4 g, 2 mmol) dissolved in water (5 ml). After 3days of agitation at ambient temperature, (NH₄)₂CO₃ is added (0.211 g,2.2 mmol, 1.1 eq.) and agitation is maintained for 30 hours. Thesolution is then acidified to pH 4 with 1N HCl and evaporated todryness. The residue is transferred into a screw-top bottle, suspendedin an HCl/MeOH solution (8 ml) and heated for 1.5 hours at 60° C. Theinsoluble salts are filtered, rinsed with MeOH and the filtrateevaporated and dried under vacuum over KOH (0.742 g). The crude mixtureof hydantoin esters is dissolved in AcOEt (20 ml), washed with asaturated solution of NaCl to which NaHCO₃ is added in order to maintaina neutral pH. The aqueous washing phase is re-extracted using AcOEt (10ml). The combined organic phases are dried over Na₂SO₄ and evaporated.Di-t-butyldicarbonate (1.5 ml, 3 eq.) and DMAP (21 mg, 0.08 eq.) areadded to the mixture of methyl esters of hydantoin dissolved in CH₃CN(25 ml). The solution is agitated overnight and rapidly purified byflash chromatography (SiO₂, 230-400 mesh, 2×10 cm, eluant CH₂Cl₂, thenCH₂Cl₂/AcOEt, 4:1), leading to a total yield of 53.5% (0.503 g, 1.07mmol). The mixture of totally protected hydantoins is treated with LIOH,HCl/AcOH, purified and separated as described previously: ACPT-I (0.062g), ACPT-II (0.096 g), (±)-ACPT-III (0.035 g). Overall yield: 38.8% withrespect to the ketodiester.

Example 5

The trans-ketodiester (±)-8 (0.2 g, 1 mmol) is treated as described inExample 1 and leads to ACPT-I (0.015 g), ACPT-II (0.02 g) and(±)-ACPT-III (0.15 g). Overall yield: 74.2% with respect to theketodiester.

Example 6

The trans-ketodiester-(−−)-(3R,4R)-8 (0.134 g, 0.67 mmol, ee>98%) istreated with (NH₄)₂CO₃/KCN, as described in Example 3 for 5 hours, thenre-esterified as described in Example 4 in order to produce a colourlessoil (0.149 g, 0.552 mmol, yield 82%) which is then treated withBoc₂O/DMAP then LiOH and HCl/AcOH and purified as described in Example3. After the cation exchanger column, a mixture is obtained (0.091 g,54.1%) essentially containing (−)-(3R,4R)-ACPT-III (97.5%) which ispurified by anion exchanger chromatography (0.083 g, 0.333 mmol, ee99.2%), and small quantities of ACPT-I (0.6%) and ACPT-II (1.9%).

(−−) (3R,4R)-ACPT-III: [α]_(D) ²²=−32.3 (c 0.73, H₂O).

Example 7

The trans-ketodiester-(+)-(3S,4S)-8 (0.172 g, 0.858 mmol, ee>99.8%) istreated as described in Example 6. After the cation exchanger column, amixture (0.109 g, 50.6%) is obtained essentially containing(+)-(3S,4S)-ACPT-III (98.2%) which is purified by anion exchangerchromatography (0.105 g, 0.451 mmol, ee 98.3%) and small quantities ofACPT-I ((0.4%) and ACPT-II (1.8%).

(+)-(3S,4S)-AcPT-III: [α]_(D) ²²=+26.4 (c 0.64, H₂O)

Example 8

Study of the Biological Activity

The biological activity of ACPT-I, -II and -III was tested ontransfected HEK 293 cells expressing mGluR1a, mGluR2 or mGluR4a, chosenas prototypes of the metabotropic receptors of groups I, II or III.

For this purpose, the activation of phospholipase C was measured(accumulation of inositol phosphates).

1) Equipment and methods

Culture and transfection of HEK 293 cells

The HEK 293 cells are cultured in a Dulbecco's modified Eagle medium(DMEM, Gibco BRL) to which 10% of foetal calf serum has been added, andtransfected by electroporation as previously described by Gomeza et al.,Molecular Pharmacology, 1996, 50:923-930 (1996).

The electroporation is carried out in a total volume of 300 μl with 10μg of supporting DNA, plasmid DNA containing mGluR1a (0.3 μg), mGluR2 (2μg) or mGluR4a (5 μg) and 10⁷ cells.

In order to allow activation of the phospholipase C by mGluR2 andmGluR4a, which effect is easier to measure than the inhibition of theproduction of cAMP, these receptors are co-expressed with chimeric G,Gqo5 and Gqi9 proteins, as described by Gomeza. The pharmacologicalprofiles of these 2 receptors determined according to this method, havealready been described as identical to those characterized by measuringthe inhibition of the formation of cAMP.

Determination of the accumulation of inositol phosphates (IP).

The determination of the accumulation of IP in transfected cells iscarried out as described by Gomeza after labelling the cells forapproximately 14 hours with [³H]-myo-inositol (23.4 Ci/mol, NEN,France).

Stimulation is carried out for 30 minutes in a medium containing 10 mMLiCl in the presence of the drugs tested. The formation of the basic IPis determined after 30 minutes of incubation in the presence of 10 mMLiCl and pyruvate glutamate transaminase (1 U/ml) degrading theglutamate (Glu) and 2 mM of pyruvate in order to avoid the possibleeffects of Glu released by the cells. The results are expressed in thequantity of IP product with respect to the radioactivity present in themembranes.

Culture and recording of the granule cells of the cerebellum

The granule cells of the cerebellum are cultured from 7 day-old babymice as described by Van-Vliet, B. J., J. of Neurochemistry, 1989, .52,1229-1239.

Recording is carried out using the technique known as a “patch clamp” inthe full cell configuration and the molecules are applied using a rapidapplication technique.

2/Results

Initially, tests were carried out in order to check whether the ACPT'swere capable of activating or exercising an antagonist effect vis-à-visthe ionotropic receptors. These tests have shown that none of the ACPTenantiomers induces a current when they are placed in contact with thegranule cells of the cerebellum at a concentration of 1 mM.

In the same batches, currents are on the contrary seen to be induced byNMDA (100 μM) or kainate (100 μM, which concentration allows activationof both the AMPA and kainate receptors), as envisaged given theactivation of the NMDA and non-NMDA receptors. The antagonist effects ofACPT-I, ACPT-II and ACPT-III (1 mM) were also examined in responsesinduced by NMDA or kainate (100 μM). No significant inhibition wasobserved with ACPT-II and ACPT-III. On the other hand, a slightinhibition was observed in the presence of ACPT-I (1 mM), of the orderof 10%, in the reponses induced by NMDA or kainate.

The effect of the different ACPT's tested was then analyzed onrepresentative mGluRs receptors of groups I, II and III, namely mGluR1a,mGluR2 and mGluR4a.

The results obtained are illustrated by FIGS. 1a to 1 c and summarizedin Table 2.

FIG. 1a indicates the accumulation of inositol phosphates (IP) inducedby these molecules (3 mM), compared with that induced with by (Glu) at aconcentration of 1 mM. In this figure, ▪ represents the basic values(IP), □ represents those measured in the presence of Glu, in thepresence of ACPT-I, in the presence of ACPT-II and in the presence ofACPT-III.

FIGS. 1b and 1 c give the IP production response, expressed in % of themaximum effect, as a function of the concentration of the medicamentused in μM.

FIG. 1b indicates the agonist effect of ACPT-I (▴) and (±)ACPT-III (∘),at different concentrations, on mGluR4a and FIG. 1c the agonist effectfor enantiomers of ACPT-III (∘: (+)ACFT-III; : (−)ACPT-III, atdifferent concentrations, on mGluR4a.

As FIG. 1a shows, none of the ACPT molecules activates MGluR1a ormGluR2.

On the other hand, ACPT-I and ACPT-III activate mGluR4a in adose-dependent manner (FIGS. 1a and 1 b ) with EC₅₀ values (effectiveconcentration producing 50% of the maximum effect), respectively, of7.2±2.3 and 40±8 μM (n=3).

It can be noted that only (+)ACPT-III has agonist properties vis-à-vismGluR4a with an EC₅₀ value of 8.8±3.2 μM (n=2) (FIG. 1c).

FIG. 2 shows the inhibition of the formation of I? induced by Glu, underthe effect of the ACPT's (the symbols are the same as in FIG. 1a).

It can be noted that ACPT-I, -II, and -III inhibit the formation of theIP's induced by the Glu in cells expressing mGluR1a. All these compoundsinduce a move to the right of the dose-response curve of the Glu asexpected for competitive antagonists.

It can be noted that the compounds ACPT-II and -III also inhibit theresponses induced by Glu in cells expressing mGluR2. This result is notobtained with ACPT-I. ACPT-II appears to be more active than ACPT-III.

It can also be noted that the ACPT-II compound also exercises anantagonist effect vis-à-vis the effect of Glu on mGluR4a and thereforeappears as a general antagonist of the metabotropic glutamatergicreceptors.

All the above results are summarized in Table 2 below where the agonist(EC₅₀, μM) or antagonist (K_(B), μM) effect of the ACPT's on themGluR1a, mGluR2 and mGluR4a receptors is indicated.

mGluR1a mGluR2 mGluR4a EC₅₀ K_(B) EC₅₀ K_(B) EC₅₀ K_(B) ACPT-I — >1000 —— 7.2 ± 2.3 — ACPT-II — 115 ± 2 — 88 ± 21 — 77 ± 9 (=)- —  >300 — >30040 ± 8  — ACPT-III (÷)- — (1000)^(a) — (150)^(a) 8.8 ± 3.2 — (3S, 4S)-ACPT-III (−)- — (1000)^(a) — (300)^(a) — 220 (3R, 4R)- ACPT-III “—”; noactivity at the highest concentration tested (3 mM). ^(a)IC₅₀ values(Glu = 20 μM for mGluR1a and mGluR2, 30 μM for mGluR4a)

FIGS. 3a to 3 c and 3 d to 3 f illustrate tee antagonist effect, and thedetermination of the inhibition constant of ACPT-II on the mGluR1areceptors (FIGS. 3a and 3 d), mGluR2 (FIGS. 3b ,and 3 e) and mGluR4a(FIGS. 3c and 3 f). FIGS. 3a to 3 c give the production of IP (withrespect to the total radioactivity, in gross values), as a function ofthe concentration of Glu in μM (logarithmic scale), used alone (control)or in the presence of a fixed concentration of ACPT-II. The symbols havethe following meanings: (), control; (□), +100 μM (200 μM for mGluR1a); (▴), +300 μM (500 μM for mGluR1a); ∘, +1000 μM.

The graphs of FIGS. 3d to 3 f show Shild's graphic representationobtained from the dose-response curves of FIGS. 3a to 3 c and give thevalues of Log(A′/A−1) as a function of Log (B), where A′ is the EC₅₀value of the Glu measured in the presence of concentration B of ACPT-IIand A, the EC₅₀ value of the Glu measured in the absence of ACPT-IT,i.e. in the absence of an antagonist.

It can be noted that the ACPT-II compound exercises a similar effect onmGluR1a, mGluR2 and mGluR4a. In each case, the slope is close to theunit as envisaged for a competitive antagonist. The respective KB valuesdetermined using Shild's representation are 115±2, 88±21, 77±9 μM (n=3)respectively for mGluR1a, mGluR2 and mGluR4a.

The effect of (+) ACPT-III and (−) ACPT-III on these receptors was alsostudied, taking into account the activity of the ACPT-III, formed by thetwo enantiomers, on mGluR1a and mGluR2.

The optional antagonist effect of the (−)ACPT-III compound on mGluR4awas also studied, given that only the (+) enantiomer is an agonist ofthis receptor as indicated above.

The results obtained are reported in FIGS. 3a to 3 c. These figuresrespectively concern the results obtained on mGluR1a, mGluR2 andmGluR4a. The symbols are the following: () antagonist effect of thecompound (+) ACPT-III and (∘) of the compound (−) ACPT-III on mGluRs.The concentrations in ACPT-III are expressed in μM units.

It can be noted that the ACPT-III (+) and (−) inhibit the Glu responses,with a low strength in the cells expressing mGluR1a or mGluR2. OnmGluR4a, the (−) ACPT-III compound exercises an antagonist effectvis-à-vis that of Glu (FIG. 4c) and analysis of the Shild curvesindicates a competitive inhibition (slope=0.877) with a K_(B) value of220 μM.

As already described with numerous other receptors coupled to Gproteins, it is possible to detect a basic activity of the mGluR1areceptor (Prézeau et al., Molecular Pharmacology, 1996, 49:422-429). Infact, even in the total absence of any agonist, an increased activity ofthe phospholipase C is detectable in cells expressing mGluR1a. However,unlike what is observed with other receptors coupled to G proteins, noneof the known competitive antagonists of mGluR1 is capable of inhibitingthe constitutive activity of this receptor. None of these moleculestherefore acts as a reverse agonist. On the other hand, the use ofACPT-II (but not of ACPT-I or ACPT-III) at a concentration of 1 mMinhibits the basal activity of mGluR1a measured either under controlconditions, or when the receptor is co-expressed with the alpha sub-unitof the Gq protein. These results are reported in FIGS. 5a and 5 b. InFIG. 5a, it can be seen that only ACPT-II significantly inhibits thebasal activity of the phospholipase C measured on HEK 293 cellsexpressing the mGluR1a receptor. FIG. 5b shows the results obtained oncells expressing mGluRla and overexpressing the alpha sub-unit of the Gqprotein. These observations show that ACPT-II is the only knownantagonist of mGluR1a endowed with a reverse agonist activity on thisreceptor.

What is claimed is:
 1. A compound which is an agonist, antagonist orreverse agonist of glutamatergic receptors, of formula (I)

in which R₁ to R₄, identical to or different from each other, representa hydrogen atom, an alkyl radical or an aryl radical, said radicalsbeing optionally substituted, R₁ and R₂ together being able to furtherrepresent a —(CH₂)_(m)— bridge, where m is an integer from 1 to 5, A₁and A₂ each represent a radical selected from the group consisting of—COOH, —SO₃H and —PO₃H₂ radicals and their amide and ester derivatives,Y represents a hydrocarbon chain —(CH₂)_(n)—, n being 0 or an integerfrom 1 to 5, said hydrocarbon chain optionally including at least oneheteroatom O, N or S.
 2. A compound according to claim 1, wherein thecarbons carrying R₁ and R₂ are not linked together to form a bridge andY is —(CH₂)_(n)— where n is
 0. 3. A compound according to claim 1,wherein the carbons carrying R₁ and R₂ are not linked by a bridge and Yrepresents a —(CH₂)_(n)— group where n is an integer from 1 to
 5. 4. Acompound according to claim 1, wherein A₁ and A₂ both represent acarboxyl group, or a derivative thereof, wherein said derivative isselected from the group consisting of ester and amide derivatives.
 5. Acompound according to claim 1, wherein R₁ to R₄ represent a hydrogenatom.
 6. A compound according to claim 1, wherein said compound is anachiral or chiral molecule in the form of a diastereoisomer.
 7. Acompound according to claim 5, wherein said compound is a1-amino-cyclopentane 1,3,4 tricarboxylic acid selected from the groupconsisting of ACPT-I, ACPT-II, ACPT-IIIa and ACPT-IIIb respectivelycorresponding to the following formulae (II), (III), (IVa) and (IVb):


8. Process for synthesizing a compound according to claim 1 comprising:reacting a ketone of formula (V)

in which R₁ to R₄ and n are as defined in formula I and A₃ and A₄represent a —COOR₅, PO₃(R₅)₂, PO₃HR₅, or SO₃R₅ group, where R₅ is ahydrogen atom or an alkyl radical, with a cyanide and a basic ammoniumcarbonate, or reacting the ketone (V) with an ammonium salt and acyanide, then adding ammonium carbonate to the reaction mixture, saidreaction producing a hydantoin of formula (VI)

followed by hydrolysis of the hydantoin thus obtained, or of a hydantionderivatives in which the —NH groups are blocked by protective groups,said hydrolysis resulting in a mixture containing variousdiastereoisomers, and separating the different compounds.
 9. Apharmaceutical composition comprising at least one compound according toclaim 1, in combination with a pharmaceutically acceptable vehicle. 10.A compound according to claim 1, wherein at least one of R₁ to R₄ is analkyl radical or an aryl radical.
 11. A compound according to claim 10,wherein said radical is substituted.
 12. A compound according to claim11, wherein said radical is substituted with a halogen atom or ahydroxyl group.
 13. A compound according to claim 3, wherein Y is ahydrocarbon chain —(CH₂)_(n)— where n is an integer from 1 to 5, saidhydrocarbon chain having at least one heteroatom O, N and/or S betweensaid (CH₂)_(n) groups when n is an integer from 2 to
 5. 14. A compoundaccording to claim 4, wherein said carboxyl group derivative is selectedfrom the group consisting of ester and amide derivatives.
 15. A compoundaccording to claim 6, wherein said diastereoisomer is racemic.
 16. Acompound according to claim 15, wherein said diastereoisomer is in theform of an enantiomer.
 17. Process according to claim 8, furthercomprising resolution of racemic diastereoisomers.
 18. A method forproducing an agonist, antagonist or reverse agonist effect on aglutamatergic receptor comprising administering a compound according toclaim 1 to a glutamatergic receptor.
 19. A method according to claim 18,wherein said glutamatergic receptor is a metabotropic glutamatergicreceptor.
 20. A method for producing an agonist, antagonist or reverseagonist effect on a glutamatergic receptor in a cell culture comprisingintroducing a compound according to claim 1 to a cell culture expressingsaid receptors.
 21. A method according to claim 20, wherein saidglutamatergic receptor is a metabotropic glutamatergic receptor.
 22. Apharmaceutical composition according to claim 9, wherein said compoundof formula I is in the form of a prodrug.
 23. A pharmaceuticalcomposition according to claim 9, wherein said compound of formula I isin the form of an amide or ester.
 24. A method for modulating an effectof glutamate in a central nervous system of a patient comprisingadministering a compound according to claim 1 in an amount effective formodulating the effect of glutamate.
 25. A method for treating acondition selected from the group consisting of memory disorders, seniledementia, epilepsy, Alzheimer's disease, Parkinson's disease, peripheralneuropathies and motor disorders in a patient comprising administeringto said patient a compound according to claim 1 in an amount effectivefor treating said condition.
 26. A pharmaceutical composition comprisingthe compound according to claim 1 in an amount effective for producingan agonist, antagonist or reverse agonist effect on a glutamatergicreceptor, in combination with a pharmaceutically acceptable vehicle. 27.A pharmaceutical composition comprising the compound according to claim1 in an amount effective for modulating an agonist, antagonist orreverse agonist effect of glutamate on the glutamatergic receptors of acentral nervous system of a patient, in combination with apharmaceutically acceptable vehicle.
 28. A pharmaceutical compositioncomprising the compound according to claim 1 in an amount effective fortreating a condition selected from the group consisting of memorydisorders, senile dementia, epilepsy, Alzheimer's disease, Parkinson'sdisease, peripheral neuropathies and motor disorders in a patient, incombination with a pharmaceutically acceptable vehicle.